Researchers in the surgical arts have been working for many years to develop new techniques and materials for use as grafts to replace or repair damaged or diseased tissue structures, particularly bones and connective tissues, such as ligaments and tendons, and to hasten fracture healing. It is very common today, for instance, for an orthopedic surgeon to harvest a patellar tendon of autogenous or allogenous origin for use as a replacement for a torn cruciate ligament. The surgical methods for such techniques are well known. Further it has become common for surgeons to use implantable prostheses formed from plastic, metal and/or ceramic material for reconstruction or replacement of physiological structures. Yet despite their wide use, surgically implanted prostheses present many attendant risks to the patient. It will suffice to say that surgeons are in need of a non-immunogenic, high tensile strength graft material which can be used for surgical repair of bones, tendons, ligaments and other functional tissue structures.
Researchers have been attempting to develop satisfactory polymer or plastic materials to serve as ligament, or tendon replacements or as replacements for other connective tissues, such as those involved in hernias and joint-dislocation injuries. It has been found that it is difficult to provide a tough, durable plastic material which is suitable for long-term connective tissue replacement. Plastic materials can become infected and difficulties in treating such infections often lead to graft failure.
In accordance with the present invention there is provided tissue graft constructs for orthopedic and other surgical applications which in experiments to date have been shown to exhibit many of the desirable characteristics important for optimal graft function.
The graft construct in accordance with this invention is prepared from a delaminated segment of intestinal tissue of a warm-blooded vertebrate, the segment comprising the tunica submucosa and basilar tissue of the tunica mucosa, most typically including the muscularis mucosa and the stratum compactum. The tunica submucosa and basilar mucosa tissue are delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of the segment of intestinal tissue. The resulting segment is a tubular, very tough, fibrous, collagenous material which is fully described in U.S. Pat. Nos. 4,902,508 issued Feb. 20, 1990 and 4,956,178 issued Sep. 11, 1990, which patents are expressly incorporated herein by reference. In those patents, the tissue graft material is primarily described in connection with vascular graft applications.
Intestinal submucosa graft material may be harvested from a biological source such as animals raised for meat production, including, for example, pigs, cattle and sheep or other warm-blooded vertebrates. Older sows having a weight between 400 and 600 lbs. have been found to be particularly good sources of graft material for use for this invention. A graft segment removed from such an older sow can have a tensile strength of up to 1700 psi in the longitudinal direction of the intestine. Thus, there is a ready source of intestinal submucosa graft material in slaughter houses around the country, ready to be harvested and utilized in accordance with the present invention.
The tri-layer intestinal segments used to form the graft constructs in accordance with this invention can be used in their delaminate tubular form or they can be cut longitudinally or laterally to form elongated tissue segments. In either form, such segments have an intermediate portion and opposite end positions and opposite lateral portions which can be formed for surgical attachment to existing physiological structures, using surgically acceptable techniques.
An advantage of the intestinal submucosa graft formed for surgical repair in accordance with the present invention is its resistance to infection. The intestinal submucosa graft material, fully described in the aforesaid patents, have high infections resistance, long shelf life and storage characteristics. It has been found that xenogeneic intestinal submucosa is compatible with hosts following implantation as vascular grafts, ligaments and tendons because of its basic composition. The intestinal submucosa connective tissue is apparently very similar among species. It is not recognized by the host's immune system as "foreign" and therefore is not rejected. Further the intestinal submucosa grafts appear to be extremely resistant to infection because of their trophic properties toward vascularization and toward endogenous tissues surgically affixed or otherwise associated with the implant graft. In fact, most of the studies made with intestinal submucosa grafts to date have involved non-sterile grafts, and no infection problems have been encountered. Of course, appropriate sterilization techniques acceptable to the Federal Drug Administration (FDA) may well be used to treat grafts in accordance with the present invention.
It has been found that unsterilized clean intestinal submucosa graft material can be kept at 4.degree. C., (refrigerated) for at least one month without loss of graft performance. When the intestinal submucosa graft material is sterilized by known methods, it will stay in good condition for at least two months at room temperature without any resultant loss in graft performance.
It has also been found that the grafts formed and used in accordance with this invention upon implantation undergo biological remodeling. They serve as a rapidly vascularized matrix for support and growth of new endogenous connective tissue. The graft material used in accordance with this invention has been found to be trophic for host tissues with which it is attached or otherwise associated in its implanted environment. In multiple experiments the graft material has been found to be remodelled (resorbed and replaced with autogenous differentiated tissue) to assume the characterizing features of the tissue(s) with which it is associated at the site of implantation. In tendon and ligament replacement studies the graft appears to develop a surface that is synovialized. Additionally, the boundaries between the graft and endogenous tissue are no longer discernible. Indeed, where a single graft "sees" multiple microenvironments as implanted, it is differentially remodeled along its length. Thus when used in cruciate ligament replacement experiments not only does the portion of the graft traversing the joint become vascularized and actually grow to look and function like the original ligament, but the portion of the graft in the femoral and tibial bone tunnels rapidly incorporates into and promotes development of the cortical and cancellous bone in those tunnels. In fact, it has been found that after six months, it is not possible to identify the tunnels radiographically. It appears that intestinal submucosa serves as a matrix for and stimulates bone regrowth (remodeling) within the tunnels. The bone tunnels with the encompassed intestinal submucosa graft have never been shown to be a weak point in the tensile-strength evaluations after sacrifice of test dogs accomplished to date.
It is one object of the present invention, therefore, to provide graft constructs for use as connective tissue substitute, particularly as a substitute for ligaments and tendons. The graft is formed from a segment of intestinal tissue of a warm-blooded vertebrate. The graft construct comprises the tunica submucosa, the muscularis mucosa and the stratum compactum of the tunica mucosa, said tunica submucosa, muscularis mucosa and stratum compactum being delaminated from the tunica muscularis and the luminal portions of the tunica mucosa of the segment of intestinal tissue. The graft construct has a longitudinal dimension corresponding to the length of the segment of intestinal tissue and a lateral dimension proportioned to the diameter of the segment of intestinal tissue. For tendon and ligament replacement, applications the resulting segment is typically preconditioned by stretching longitudinally to a length longer than the length of the intestinal tissue segment from which it was formed. For example, the segment is conditioned by suspending a weight from said segment, for a period of time sufficient to allow about 10 to about 20% elongation of the tissue segment. Optionally, the graft material can be preconditioned by stretching in the lateral dimension. (The graft material exhibits similar viscoelastic properties in the longitudinal and lateral dimensions). The graft segment is then formed in a variety of shapes and configurations, for example, to serve as a ligament or tendon replacement or substitute or a patch for a broken or severed tendon or ligament. Preferably, the segment is shaped and formed to have a layered or even a multilayered configuration with at least the opposite end portions and/or opposite lateral portions being formed to have multiple layers of the graft material to provide reinforcement for attachment to physiological structures, including bone, tendon, ligament, cartilage and muscle. In a ligament replacement application, opposite ends are attached to first and second bones, respectively, the bones typically being articulated as in the case of a knee joint. It is understood that ligaments serve as connective tissue for bones, i.e., between articulated bones, while tendons serve as connective tissue to attach muscle to a bone.
When a segment of intestine is first harvested and delaminated as described above, it will be a tubular segment having an intermediate portion and opposite end portions. The end portions are then formed, manipulated or shaped to be attached, for example, to a bone structure in a manner that will reduce the possibility of graft tearing at the point of attachment. Preferably it can be folded or partially everted to provide multiple layers for gripping, for example, with spiked washers or staples. Alternatively, the segment may be folded back on itself to join the end portions to provide a first connective portion to be attached, for example, to a first bone and a bend in the intermediate portion to provide a second connective portion to be attached to a second bone articulated with respect to the first bone.
For example, one of the end portions may be adapted to be pulled through a tunnel in, for example, the femur and attached thereto, while the other of the end portions may be adapted to be pulled through a tunnel in the tibia and attached thereto to provide a substitute for the natural cruciate ligament, the segment being adapted to be placed under tension between the tunnels to provide a ligament function, i.e., a tensioning and positioning function provided by a normal ligament.
The intestinal submucosa segment, which in its preferred embodiment consists essentially of the tunica submucosa, muscularis mucosa and stratum compactum, has been found to have good mechanical strength characteristics in the same delaminated tubular form in which it is produced following the described delamination procedure. It has been found that having,the stratum compactum layer inside the tubular form in a tendon or ligament graft provides good trophic properties for vascularization. It is believed that grafts used in accordance with the present invention with the intestinal segment inverted, i.e., with the stratum compactum on the outside will exhibit like functionality, but further testing is required to determine the vascularization characteristics with that structure utilized, for example, as a tendon or ligament graft.
Another object of the present invention is to provide a method for surgical repair of diseased or damaged tissues connecting first and second tissues structures selected from the group consisting of bone, ligament, tendon, cartilage and muscle. The method comprises the step of attaching the first and second structures to opposite end portions or opposite lateral portions of a tissue graft construct formed in accordance with the above described embodiments. The graft comprises the tunica submucosa, the muscularis mucosa and the stratum compactum of a segment of intestinal tissue of a warm-blooded vertebrate, said tunica submucosa, muscularis mucosa and stratum compactum being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of said intestinal tissue.
Because grafts used in orthopedic applications are typically placed under tension in their surgical installation, it may be preferable to combine two or even more tissue Segments to provide a multi-ply (multi-layered) graft construct. It is another object of the present invention, therefore, to provide such grafts in which two or more intestinal segments are arranged to have their end portions joined together with the joined end portions and/or lateral portions adapted to be attached to a bone, tendon, ligament or other physiological structure. One method for providing a double intestinal segment may be to pull one tubular segment internally within another segment to provide a double-walled tube, the joined ends of which can be attached, for example, to a bone, tendon or ligament. These doubled segments will provide enhanced tensile strength and resistance to stretching under tension.
A further object of the present invention is to provide such a graft in which one of said end portions is adapted to be pulled through a tunnel in, for example, the femur and attached thereto and the other of said end portion is adapted to be pulled through a tunnel in the tibia and attached thereto to provide a substitute for the natural cruciate ligament, the segment being adapted to be placed under tension between the tunnels to provide a ligament function. Similar procedures can be employed to provide ligament function to other articulating bones.
Still a further object of the present invention is to provide an orthopedic graft for use as connective tissue to hold fractured bone pieces together and in proper orientation in the body, the segment being formed to serve as a fracture wrap about segments of fractured bone and to be attached to the bone.
One other object of this invention is to provide a method for promoting the healing and/or regrowth of diseased or damaged tissue structures by surgically repairing such structures with a tissue graft construct prepared from a segment of intestinal submucosal tissue as described above. The implanted graft construct is trophic toward vascularization and differentiated tissue growth and is essentially remodelled to assume the structural and functional characteristics of the repaired structure.
Other objects and features of the present invention will become apparent as this description progresses.